Hereditary combined deficiency of the vitamin K-dependent clotting factors.

Hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X as well as natural anticoagulants protein C, protein S and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting, and usually involve the skin and mucosae. A range of non-haemostatic symptoms are often present, including developmental and skeletal anomalies. VKCFD is an autosomal recessive disorder caused by mutations in the genes of either gamma-glutamyl carboxylase or vitamin K2,3-epoxide reductase complex. These two proteins are necessary for gamma-carboxylation, a post-synthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of non-haemostatic proteins. Diagnostic differentiation from other conditions, both congenital and acquired, is mandatory and genotype analysis is needed to confirm the defect. Vitamin K administration is the mainstay of therapy in VKCFD, with plasma supplementation during surgery or severe bleeding episodes. In addition, prothrombin complex concentrates and combination therapy with recombinant activated FVII and vitamin K supplementation may constitute alternative treatment options. The overall prognosis is good and with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.

Novel splice site mutations in the gamma glutamyl carboxylase gene in a child with congenital combined deficiency of the vitamin K-dependent coagulation factors (VKCFD).

Congenital combined deficiency of the vitamin K-dependent coagulation factors is a rare bleeding disorder caused by either a defect in the gamma-glutamyl carboxylase or the vitamin K epoxide reductase enzyme complex. The diagnosis should be considered when vitamin-K dependent factor activities are decreased and liver dysfunction, vitamin K deficiency, and factitious coumarin ingestion have been excluded. We report a case of VKCFD in a child resulting from compound heterozygosity for two novel splice site mutations of the gamma-glutamyl carboxylase gene. Oral vitamin K supplementation resulted in partial resolution of proteins and complete resolution of bleeding.

Vitamin K, an update for the paediatrician.

INTRODUCTION: This review summarizes current knowledge on vitamin K for the paediatrician. Vitamin K is a fat-soluble vitamin, present in plants as phylloquinone and produced by bacteria as menaquinone. It is acting as a co-factor for gamma-glutamyl carboxylase. This enzyme is responsible for post-translational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation; others play a role in calcium homeostasis. DATA: Newborn babies are at particular risk of vitamin K deficiency, as placental transfer is limited and human milk is a poor source. Vitamin K prophylaxis at birth effectively prevents vitamin K deficiency bleeding (VKDB), formerly known as "haemorrhagic disease of the newborn". Recent epidemiological studies provide data on the effectiveness of different administration routes and dosing schemes. Infants of mothers taking drugs that inhibit vitamin K are at risk of early VKDB and should receive 1 mg intramuscular (i.m.) as soon as possible after birth. Classic VKDB is prevented by intramuscular as well as by oral administration of 1 mg vitamin K. In exclusively breast-fed infants, single i.m. administration at birth is also effectively preventing (rare) late VKDB but single oral administration is not. If given orally, prophylaxis should be continued by either weekly administration of 1 mg till 12 weeks or repeating 2 mg at weeks 1 and 4. Daily administration of 25 microg offers insufficient protection. The only infants not fully protected in this way are those with yet unrecognised liver disease. CONCLUSIONS: Further work is needed before firm recommendations can be made regarding dose in preterm infants and in patients with fat malabsorption/cholestasis or regarding the role of vitamin K in the prevention of osteoporosis.

Congenital vitamin K-dependent coagulation factor deficiency: a case report.

Congenital vitamin K-dependent coagulation factor deficiency is a very rare bleeding disorder, which usually presents with episodes of intracerebral bleed in the first few weeks of life, sometimes leading to a fatal outcome. We report a case of combined factor deficiency of vitamin K-dependent factors in which the patient presented with both intracerebral bleeding, and possibly also thrombosis, and responded to a vitamin K supplement along with fresh frozen plasma.

Vitamin K deficiency during the perinatal and infantile period.

Coagulation-related plasma proteins develop slowly during the gestational period and are still markedly lower than normal at birth. Great interest exists in the status of the vitamin K-dependent procoagulant factors (factors II, VII, IX and X) because a number of healthy newborns develop postpartum a bleeding tendency that is due to vitamin K deficiency. The most serious cases involve intracranial bleeding with convulsions, coma and potential death. Typically, these infants have markedly prolonged prothrombin times that shorten following the administration of vitamin K. A common feature of these infants is that they are breast-fed, although other factors, especially hepatobiliary diseases, contribute to this disorder. Vitamin K deficiency bleeding can develop as early as in the first 24 hours after birth, but most infants are diagnosed between days 2 and 7 postpartum. Late forms (> 1 week and up to 6 months) are also noted. This deficiency can be compensated for by prophylactically administering vitamin K to the newborns or by bottle-feeding. Although vitamin K2 may pass in small quantities through the placenta, it is insufficient to make up for the deficit. The first dose of vitamin K can also be given orally to the newborn after one or two regular feedings, and the second dose can be administered upon discharge from the hospital. A problem that remains to be solved is the late development of vitamin K deficiency in spite of prophylaxis at birth.

Differences in reactivity to vitamin K administration of the vitamin K-dependent procoagulant factors, protein C and S, and osteocalcin.

Vitamin K is a trace nutrient necessary not only for the synthesis of four plasma clotting factors but also the production of two important anticlotting factors, protein C and protein S, and the synthesis of two bone proteins. If protein C and protein S are produced more quickly and/or in higher quantities than four plasma coagulation factors after vitamin K administration, then the result is unfavorable for stopping of hemorrhage. We therefore studied the difference of time dependence of prothrombin procoagulant factors, protein C and S and bone Gla protein after the administration of vitamin K in normal and vitamin K-deficient neonates. Results of our study showed that, on the whole, coagulation factors increased markedly more than anticlotting factors after vitamin K administration. Furthermore, the increase in bone Gla protein was also higher compared with protein C activity, although the detailed mechanism of the difference in reactivity of prothrombin procoagulant factors, protein C and S and bone Gla protein to vitamin K administration is not clear.

Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex.

Hereditary combined deficiency of the vitamin K dependent coagulation factors is a rare bleeding disorder. To date, only eleven families have been reported in the literature. The phenotype varies considerably with respect to bleeding tendency, response to vitamin K substitution and the presence of skeletal abnormalities, suggesting genetic heterogeneity. In only two of the reported families the cause of the disease has been elucidated as either a defect in the gamma-carboxylase enzyme (1) or in a protein of the vitamin K 2,3-epoxide reductase (VKOR) complex (2). Here we present a detailed phenotypic description of two new families with an autosomal recessive deficiency of all vitamin K dependent coagulation factors. In both families offspring had experienced severe or even fatal perinatal intracerebral haemorrhage. The affected children exhibit a mild deficiency of the vitamin K dependent coagulation factors that could be completely corrected by oral substitution of vitamin K. Sequencing and haplotype analysis excluded a defect within the gamma-carboxylase gene. The finding of highly increased amounts of vitamin K epoxide in all affected members of both families indicated a defect in a protein of the VKOR-multienzyme-complex. Further genetic analysis of such families will provide the basis for a more detailed understanding of the structure-function relation of the enzymes involved in vitamin K metabolism.

Acarboxy prothrombin (PIVKA-II) in cord plasma in the south of Thailand.

Acarboxy prothrombin or PIVKA-II (protein induced by vitamin K absence or antagonist-II) was used to determine the presence of vitamin deficiency in newborn infants. Of 230 cord blood samples assayed by using ELISA method, 34.8 per cent were positive for PIVKA-II 0.13-17 AU/ml. The positive rate for PIVKA-II was greater in infants of primigravida (50.7%) than in those of multigravida (27.9%). All infants received prophylactic vitamin K, and no infant with positive PIVKA-II in cord blood subsequently had clinical bleeding. Because of the high prevalence of vitamin K deficiency in newborn infants in the South of Thailand, all newborn infants should receive prophylactic vitamin K at birth.

Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives.

We have evaluated a boy who had excessive bleeding and bruising from birth and showed markedly prolonged prothrombin times, partially correctable by oral vitamin K administration. Additional laboratory studies demonstrated decreased activities of plasma factors II, VII, IX, and X; near normal levels of immunologically detected and calcium binding-independent prothrombin; undercarboxylation of prothrombin; excess circulating vitamin K epoxide; decreased excretion of carboxylated glutamic acid residues; and abnormal circulating osteocalcin. These results all are consistent with effects resulting from decreased posttranslational carboxylation secondary to an inborn deficiency of vitamin K epoxide reductase. This individual also had nasal hypoplasia, distal digital hypoplasia, and epiphyseal stippling on infant radiographs, all of which are virtually identical to features seen secondary to first-trimester exposure to coumarin derivatives. Therefore, by inference, the warfarin embryopathy is probably secondary to warfarin's primary pharmacologic effect (interference with vitamin K-dependent posttranslational carboxylation of glutamyl residues of various proteins) and may result from undercarboxylation of osteocalcin or other vitamin K-dependent bone proteins.

Vitamin K in the newborn: influence of nutritional factors on acarboxy-prothrombin detectability and factor II and VII clotting activity.

The incidence of acarboxy-prothrombin and the clotting activity of factors II and VII were evaluated on the fifth day of life in 183 healthy newborns, who had received no vitamin K prophylaxis. Acarboxy-prothrombin was detected in 93/183 newborns. All acarboxy-prothrombin-negative babies had factors II and VII clotting activities above 25% whereas a great variability was observed in acarboxy-prothrombin-positive babies: 21/93 had factor II and 14/93 had factor VII activities below 25%. Seventy-two of the acarboxy-prothrombin-positive babies had normal factor II and VII clotting times on the fifth day of life. These babies must be suspected to have had vitamin K deficiency on one of the first 4 days, as acarboxy-prothrombin has a 50% disappearance rate of 50 h. Acarboxy-prothrombin was mainly observed in breast-fed infants (84/122) and only rarely detectable in infants receiving supplementary (7/44) or exclusive formula feeding (2/17). The type of milk feeding however might be less important for the babies' vitamin K supply than the actual milk intake. All acarboxy-prothrombin-positive babies had received small amounts of milk on the first 4 days of life. In those with low factor II and VII clotting activities the milk intake was low throughout the first 4 days of life, whereas babies with acarboxy-prothrombin and and normal clotting activities had increased their milk intake to more than 100 ml on the third and fourth day of life. Recommendations for vitamin K prophylaxis in newborns should be given with regard to the feeding on the first days of life.

[Blood coagulation in newborns (author's transl)]. / Gerinnungsprobleme bei Neugeborenen

This article gives a survey of the physiology of blood coagulation in newborn infants, subdivided into the particularities of the plasmic coagulation system and the fibronolysis. Etiology, diagnosis and therapy of the consumption coagulopathy as well as the coagulopathy of production are dealed with.